Diabetes mellitus (hereinafter “diabetes”) presents a growing worldwide health problem. It is estimated that more than 135 million people suffer from the disease. Type 2 diabetes, also known as non-insulin-dependent diabetes (NIDD) or adult-onset diabetes, accounts for approximately 90-95% of these cases. It is expected that this number will increase 4-5% annually. Serious health problems associated with diabetes include blindness, renal disease, neuropathy, amputation, cardio-vascular disease, stroke and increased risk of mortality. The cost of treating diabetics in the United States alone is estimated be approximately $132 billion per year. Limited resources present a challenge to clinicians to provide comprehensive care to diabetic patients (Florence et al., American Family Physician 59(10):2835 (1999)). Thus, there is a significant need for more effective treatment of diabetes.
Type 2 diabetes is linked to obesity, and is characterized by insulin resistance or an inability to respond properly to one's own insulin. In non-diabetic subjects, insulin promotes cellular uptake of glucose from the blood, thereby lowering blood sugar levels while, at the same time, promoting anabolic reactions such as the cellular synthesis of glycogen, fatty acids and proteins (Stryer, 1981, Biochemistry, W.H. Freeman and Company, San Francisco).
Resistance to the metabolic actions of insulin is a hallmark of type 2 diabetes. Insulin resistance is characterized by impaired uptake and utilization of glucose in insulin sensitive target organs such as adipocytes and skeletal muscle, and impaired inhibition of hepatic glucose output. The functional insulin deficiency and the failure of insulin to suppress hepatic glucose output results in fasting hyperglycemia. Pancreatic β-cells compensate, at first, for the insulin resistance by secreting increased levels of insulin. However, the β-cells are unable to maintain the high output of insulin and eventually the glucose-induced insulin secretion falls, leading to the deterioration of glucose homeostasis and to subsequent development of overt diabetes.
While the exact cause of type 2 diabetes remains unknown, in vitro results suggest that the interruption of the insulin induced signaling cascade may be associated with elevated levels of the ganglioside GM3. It has also been suggested that the cytokine tumor necrosis factor-α (TNF-α), implicated in insulin resistance, results in increased expression of GM3 (Tagami et al., J. Biol. Chem. 277(5):3085 (2002)). Intriguingly, mutant mice lacking GM3 synthase, and thus lacking in GM3, are protected from insulin resistance caused by a high-fat diet (Yamashita et al., Proc. Natl. Acad. Sci. USA 100:3445-3449 (2003)).
Gangliosides such as GM3 are sphingolipids comprised of ceramide and at least one acidic sugar. Gangliosides are generally found in the outer leaflet of the plasma membrane (Nojri et al., Proc. Natl. Acad. Sci. USA 83:782 (1986)). They are involved in cell signaling and act as modulators of receptor activity (Yamashita et al., Proc. Natl. Acad. Sci. USA 100(6):3445 (2003)).
GM3 consists of a ceramide molecule linked to a trisaccharide consisting of glucose linked to galactose which in turn is linked to the acidic sugar N-acetylneuraminate. GM3 is synthesized in the cell by the enzymatic step-wise addition of activated sugar molecules to a ceramide molecule. The first step in the biosynthesis of GM3 is the addition of glucose to ceramide to form glucosylceramide. This step is catalyzed by the enzyme glucosylceramide synthase. In the second step, a galactose moiety is added to form lactosylceramide, followed by the addition of sialic acid to the terminal galactose residue of lactosylceramide to form GM3.
Regulation of GM3 levels, e.g., by the inhibition of glucosylceramide synthase, has been proposed as a method of treating Gaucher's disease (see, e.g., U.S. Pat. No. 6,569,889). Two types of glucosylceramide synthase inhibitors have been described for treating lysosomal storage diseases such as Gaucher's disease. Both are enzyme substrate analogs which bind to the enzyme active site and prevent substrate binding. The first type of inhibitors are ceramide analogs (see, e.g., U.S. Pat. Nos. 6,569,889; 6,255,336; 5,916,911; 5,302,609; Lee et al., J. Biol. Chem. 274(21):14662 (1999)). The second type of inhibitors are sugar analogs (see, e.g., U.S. Pat. Nos. 6,660,749; 6,610,703; 5,472,969; 5,525,616; Overkleef et al., J. Biol. Chem. 273(41):26522 (1998)).
The instant invention provides methods for treating diabetes with inhibitors of glycosphingolipid synthesis as therapeutic agents for diabetes.